CN102633686A - Preparation method of peramivir - Google Patents
Preparation method of peramivir Download PDFInfo
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- CN102633686A CN102633686A CN2011100347579A CN201110034757A CN102633686A CN 102633686 A CN102633686 A CN 102633686A CN 2011100347579 A CN2011100347579 A CN 2011100347579A CN 201110034757 A CN201110034757 A CN 201110034757A CN 102633686 A CN102633686 A CN 102633686A
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Abstract
The invention discloses a preparation method of an antiviral drug of peramivir, which is characterized in that 2-diazabicyclo [2.2.1] hept-5-en-3-one is used as an initial raw material for peramivir synthesis, and the overall yield is up to 35%. Compared with the prior art, the method has the advantages of high yield, fewer 'three wastes', safe and convenient operations, high purity of the obtained finished products, easy realization of industrial production, and the like.
Description
Technical field
The present invention relates to technical field of medicine synthesis, specifically, relate to a kind of preparation method of antiviral RWJ 270201.
Background technology
RWJ 270201 (Peramivir); Chemistry (1S by name; 2S, 3R, 4R)-3-[(1S)-1-(kharophen)-2-ethyl-butyl]-4-guanidine and-2-hydroxy-cyclopentane-1-carboxylic acid trihydrate (shown in structural formula 1); Being a kind of pentamethylene neuraminidase inhibitor by the development of U.S. biocrystal company, is the treatment of influenza medicine of the first intravenous route medication in the world.This medicine can effectively suppress duplicating and propagating of various strains of influenza viruses, has advantages such as better tolerance, toxicity are little, and promotes listing in 2010 in Japan by Japanese Shionogi company, is used for the treatment of A type (first type), Type B (B-mode) influenza infection disease.
At present, the synthesis technique of RWJ 270201 report is actually rare.Patent CN1282316A discloses a kind of technical scheme (seeing shown in the route 1) for preparing the RWJ 270201 bullion.This scheme is for so that the 2-azabicyclo [2.2.1] of chirality heptan-5-alkene-3-ketone is raw material; Through hydrochloric acid/methyl alcohol open loop, amido protecting, the addition cyclization, again hydro-reduction under the platinum dioxide catalysis, acetylize, deaminizating protection, on the synthetic route of carbonamidine, hydrolysis make RWJ 270201.This route conduct report the earliest about RWJ 270201 preparation technology; Have well with reference to property, used hypertoxic phenylcarbimide and a kind solvent benzene but its shortcoming is the cyclization step, the catalytic hydrogenation process is used expensive platinum dioxide catalysis; Cyclization, reduction step gained midbody need its diastereomer of column chromatography for separation; Not only complex operation, cost are too high, and total recovery is merely 21.6%, in suitability for industrialized production, lack competitive edge.
Route 1
Patented claim CN101538288A discloses 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone and has prepared the RWJ 270201 key intermediate through the method for open loop, esterification, reductive ring open in addition; The maximum deficiency of this method is: the reductive agent Lithium Aluminium Hydride is being prone to fire burns in a humid environment; On producing, there is bigger potential safety hazard, can't realizes serialization and mass-producing.
Document J.Org.Chem.2003,68,6591-6596 has reported by 2-ethyl butyraldehyde and has made 2-ethyl butyraldehyde oxime, improves one's methods with compound 1 cyclization in Youxiaolin/methylene dichloride system, shown in route 2 again.This method is similar with route 1, though do not use phenylcarbimide and benzene, because spatial selectivity is relatively poor, by product is more, and compound 2 needs column chromatography purification, and the cyclization yield is merely 61%.
Route 2
Summary of the invention
Long in order to solve the route for preparing in the existing gordian technique of RWJ 270201; Total recovery is low; Complex operation, the heavier deficiency that waits of the reagent environmental pollution that relates to, committed steps such as divided ring of the present invention, cyclization, reduction are improved; A kind of novel process for preparing RWJ 270201 is provided, and its operational path is as follows:
That is, be starting raw material with 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone and 2-ethyl butyraldehyde, process:
Step (a) gets midbody 1 with 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone with chlorinating agent open loop, fractionation, salify, protects amino midbody 2 again;
Step (b) with 2-ethyl butyraldehyde and oxammonium hydrochloride react midbody 3.
Step (c) in Youxiaolin/non-polar solvent system, with the cyclization of step (a)/(b) gained midbody, hydrolysis, acidifying, salify resterification midbody 5,
Step (d) midbody 5 reductive ring open under the reductive agent effect gets midbody 6,
Step (e) midbody 6 gets midbody 7 through acetylize, deaminizating protection, hydrolysis, last carbonamidine again;
Step f) midbody 7 recrystallizations get the RWJ 270201 finished product.
In the preferred embodiment of the invention, the described chlorinating agent of step (a) is selected from sulfur oxychloride; Described resolving agent is selected from tartrate, camphorsulfonic acid, glycocoll;
In embodiments of the invention, step (c) comprising: midbody 3 and midbody 2 are mixed in the non-polar solvent, drip the chlorine bleach liquor; Addition cyclization under certain temperature; Basic hydrolysis in alcoholic solvent again, organic solvent extraction is used in acidifying; After make it become tert-butylamine salt, esterification gets midbody 5;
In preferred version of the present invention, the described non-polar solvent of step (c) is selected from hexanaphthene, sherwood oil, heptane, toluene; Described ring-closure reaction temperature is-10-20 ℃; Described alcoholic solvent is selected from methyl alcohol, ethanol, Virahol, propyl carbinol; Described acidifying is acidifying under hydrochloric acid, sulfuric acid, formic acid, acetic acid existence condition; Described alkali is selected from sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood, sodium hydrogencarbonate; Described organic solvent is selected from methylene dichloride, chloroform, acetonitrile, ETHYLE ACETATE, ethyl formate, MTBE, toluene;
In preferred version of the present invention, the described reductive agent of step (d) is selected from Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN, lithium aluminium hydride, (2-methoxy ethoxy) sodium aluminate toluene solution (red aluminum solutions).
In preferred version of the present invention, the described deaminizating of step (e) protection is meant to be carried out under hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, Hydrogen bromide existence condition;
In a preferred embodiment of the invention, step (f) described recrystallization is meant and in the mixed solvent of alcoholic solvent and water, carries out, most preferably, is selected from the methanol mixed solvent.
In embodiment provided by the invention, most preferably, the described chlorinating agent of step (a) and 2-azabicyclo [2.2.1] heptan-mol ratio of 5-alkene-3-ketone is 0.5: 1-0.7: 1;
In embodiment provided by the invention, most preferably, the mol ratio of step (b) described 2-ethyl butyraldehyde oxime and midbody 2 is 2.2: 1-2.6: 1.
In embodiment provided by the invention, most preferably, the concentration range of the described aqueous sodium hypochlorite solution of step (c) is 5%-12%, preferred 9%-12%.
In preferred version of the present invention, the Youxiaolin in the described aqueous sodium hypochlorite solution of step (c) and the mol ratio of midbody 2 are 2.5: 1-3.5: 1;
In preferred version of the present invention, the dropping time of the described slow dropping of step (c) is at least 1h, is preferably 3-4h.
Most preferably, the preparation method of RWJ 270201 provided by the invention is:
Step a): with 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone with the sulfur oxychloride open loop after esterification, split salify through tartrate again, midbody 1, amino the midbody 2 of protection midbody 1;
Step b):, generate midbody 3 with 2-ethyl butyraldehyde and oxammonium hydrochloride reaction;
Step c): in Youxiaolin/non-polar solvent system, hydrolysis under cyclization, alkaline condition, acidifying, again with the TERTIARY BUTYL AMINE salify, midbody 4; Midbody 4 gets midbody 5 through free, esterification;
Step d): midbody 5 in red aluminum solutions, reduce midbody 6;
Step e): midbody 6 gets midbody 7 through acetylize, deaminizating protection, hydrolysis, last carbonamidine;
Step f): recrystallization midbody 7 gets the RWJ 270201 finished product.
Compared with prior art, useful technique effect of the present invention is embodied in:
At first, 2-azabicyclo [2.2.1] heptan in the step (a)-5-alkene-3-ketone through open loop, split and make midbody 1, the absolute configuration of this midbody will directly have influence on the quality of RWJ 270201 finished product, it is very crucial that the accurate dropping of control hydrogenchloride then seems.The method of the disclosed logical hydrogen chloride gas of CN1358170, owing to can't accurately control the hydrogenchloride consumption, and form inhomogeneous reaction with liquid phase reaction liquid, the gained resolved product often needs recrystallizing and refining, has increased the operation easier in the suitability for industrialized production.The disclosed dropping concentrated hydrochloric acid of CN101538228 methyl alcohol is introduced the method for hydrogenchloride, has increased solvent load, influences the yield of resolved product.The present invention adopts the mode that drips cheap sulfur oxychloride that is easy to get and methyl alcohol reaction introducing hydrogenchloride, even the consumption of hydrogenchloride is accurately controlled, need not to increase solvent load again, and the gained resolved product need not to make with extra care, ee＞99.5%, and stable yield is more than 92%.Not easy to operate in the prior art, products therefrom yield and second-rate shortcoming have effectively been overcome.
The second, cyclization product (3aR, 4R, 6S; 6As)-(+)-4-{ [(1,1-dimethyl-oxyethyl group) carbonyl] amino }-3-(1 '-ethyl propyl)-3a, 5,6; 6a-tetrahydrochysene-4H-pentamethylene also [d] isoxzzole-6-carboxylate methyl ester (midbody 5) synthesize an oxidation annulation (shown in following) because the spatial isomerism gunn can be followed the diastereomer (5A that generates midbody 5 in the process; 5B, 5C), prior art single step yield is up to 70%.
CN1282316A adopts phenylcarbimide and 2-ethyl-1-nitrobutane to prepare aldoxime; In benzene with (column chromatography for separation obtains midbody 5 for 1S, the 4R) 4-amino cyclopentyl-sour methyl esters of 2-alkene-1-(midbody 2) cyclization; The maximum deficiency of this method has been to use hypertoxic benzene cyanogen and benzene; Safety precaution and liquid waste disposal are also had high requirement, and the column chromatography operation also directly influences production efficiency, does not have industrial advantages.Document J.Org.Chem.2003,68,6591-6596 then is with midbody 2 and the above cyclization of backflow 20h in Youxiaolin/methylene dichloride system of 2-ethyl butyraldehyde oxime; Though do not use the benzene cyanogen and the benzene of severe toxicity; But because spatial selectivity is relatively poor, by product is more, and midbody 5 needs column chromatography purification; The cyclization yield is merely 61%, also less being used.CN1367776A then makes 2-ethyl-N--hydroxyl fourth imido acyl chloride with 2-ethyl butyraldehyde through oximate, chlorination two-step reaction, in toluene/triethylamine system, with midbody 2 cyclizations, makes with extra care through hydrolysis, acidifying, one-tenth tert-butylamine salt; The esterification step makes midbody 5 effectively separated with its diastereomer, though avoided the column chromatography operation, also is the common methods of preparation cyclization product; But Synthetic 2-ethyl-N-hydroxyl fourth imido acyl chloride has increased reactions step; And 2-ethyl-N-hydroxyl fourth imido acyl chloride has stronger tearing property, from the security consideration of environmental angle and operation, should avoid the use of such midbody; Temperature of reaction is more than 60 ℃ in addition; Promoted the generation of diastereomer, causing the midbody 5 and the ratio of diastereomer content is 75: 25, and yield is merely 63.8%.Be not difficult to find through above elaboration, how control spatial selectivity, reduce the generation of side reaction, reduce operation easier and become the key that improves cyclization product quality and yield.
The present invention is through a large amount of comprehensive and systematic experimental studies; Find (1S, 4R) 4-amino cyclopentyl-sour methyl esters of 2-alkene-1-(midbody 2) and 2-ethyl butyraldehyde oxime (midbody 3) are in the Youxiaolin/heptane system of enough high densitys, with suitable rate of addition and temperature of reaction; Can effectively suppress the generation of diastereomer; Content of isomer is merely 11% in the system, and cyclization product bullion can directly be separated out from reaction solution, purity＞98%.The gained bullion is becoming salt refining according to prior art, and calculate total recoverys with midbody 2 and can reach 80%, purity＞99.5%, diastereomer (5A content is all less than 0.01%, 5B, 5C does not detect).The present invention does not relate to severe toxicity and pungency reagent, and required 2-ethyl butyraldehyde oxime only needs one step of 2-ethyl butyraldehyde to make, and compares with prior art, has shortened reactions step, and the consumption of reaction solvent and nearly one times of minimizing have effectively been controlled " three wastes " discharging; Reaction conditions is gentle, and 20-30 ℃ of reaction 6-7h gets final product, and shortened the reaction times, reduced energy consumption, and highly purified bullion has great industrial applications prospect also for becoming salt refining to alleviate pressure.
And, the preparation of reductive ring open step (1S, 2S, 3S; 4R, 1 ' S)-3-[(1 '-amino-2 ' ethyl) butyl]-4-{ [(1,1-dimethyl-oxyethyl group) carbonyl] amino }-2-hydroxy-cyclopentane-1-carboxylate methyl ester (midbody 6), patent CN1367776A discloses Peng Qinghuana/nickelous chloride reduction (3aR; 4R, 6S, 6As)-(+)-4-{ [(1; 1-dimethyl-oxyethyl group) carbonyl] amino }-3-(1 '-ethyl propyl)-3a, 5,6; 6a-tetrahydrochysene-4H-pentamethylene is improving one's methods of [d] isoxzzole-6-carboxylate methyl ester (midbody 5) also, and the raw material type that this method relates to is more, and reaction finishes needs to drip sodium nitrite in aqueous solution separation reduzate; And in actually operating, there is potential safety hazard in the often thickness curing of reaction solution this moment; The aftertreatment many places need accurately control pH, more difficult continuous operation; The reduzate treating process needs under heating condition, to use repeatedly repetitive scrubbing organic phase of a large amount of ammoniacal liquor, and ammoniacal liquor violent volatilization under heating causes very big pollution to environment; And because the alkalescence of ammoniacal liquor is stronger, under 80 ℃ of conditions, can make the chiral carbon atom C1 ' of partial reduction product and C3 that racemization takes place, cause the loss of product, yield is the highest to be merely 73%.CN101538228A discloses the stronger Lithium Aluminium Hydride of reducing power and has made reductive agent; Though improved reaction conversion ratio; Yield reaches 80%, but that its disadvantage is a Lithium Aluminium Hydride is extremely unstable in air, very easily fire burns and blast; On producing, there is bigger potential safety hazard, can't realizes serialization and mass-producing.CN1282316A discloses the method for platinum dioxide shortening, and reaction process need keep the airtight and quick stirring of container, and equipment and safety precaution are had high requirement; The catalyst system therefor platinum dioxide costs an arm and a leg, and can make the protection of partial reaction thing deaminizating under concentrated hydrochloric acid exists, and the gained reduzate needs column chromatography for separation, and yield is low, and is of poor quality, is difficult to be applied to suitability for industrialized production.From multifactor considerations such as reaction safety, cost, environment protection, energy-saving and emission-reduction, the present invention attempts making reductive agent with two (2-methoxy ethoxy) the sodium aluminate toluene solutions (red aluminum solutions) of the dihydro of 70% weight, has obtained splendid effect.The reductive agent that the reducing power of red aluminum solutions is more general (Peng Qinghuana) is strong, is of value to the raising of reaction conversion ratio; And than Lithium Aluminium Hydride, red aluminium is owing to be toluene solution, and is comparatively stable in air, can pump delivery, improved the security and the accessibility of producing greatly.The present invention drops to the toluene solution of the toluene of midbody 5 in the red aluminum solutions, and reductive ring open is used the sal glauberi cancellation, and recrystallization promptly gets reduzate.The gentle safety of reaction conditions, easy and simple to handle, non-exhaust emission; Related solvent is single, and last handling process need not ammoniacal liquor heating repetitive scrubbing organic phase, has significantly reduced the generation of side reaction; The quality of gained reduzate is good, and yield is promoted to 82% by existing 73%.
Embodiment
Following embodiment will do further explanation to the present invention, but the present invention is not limited only to these embodiment, the scope that these embodiment do not limit the present invention in any way.Some change that those skilled in the art has done in the claim scope or adjustment also should be thought and belong to scope of the present invention.
Embodiment 1:L-tartrate (1S, 4R) preparation of 4-amino cyclopentyl-sour methyl esters of 2-alkene-1-(midbody 1)
(100.0g 0.916mol) is dissolved in 150g methyl alcohol, and temperature control 60-70 ℃, dripping thionyl chloride (65.4g, 0.6 equivalent) is dripped and finished, and backflow 30min is cooled to 20-25 ℃ with reaction solution with (±)-2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone.Add L-tartrate 84g and water 65.0g successively, temperature control 35-40 ℃ adds triethylamine 62.2g, stirs 10-15min, and (1S, 4R) 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester crystal is as crystal seed to add a small amount of L-tartrate.This mixture is cooled to 22-25 ℃, filters.Use the cold methanol wash solids, the 40 ℃ of vacuum-dryings of reducing pressure.
Obtain target compound 122.5g, yield 91.8%, HPLC record ee＞99.5%; Mp:175.0-175.5 ℃; [α] D20 ℃=-41.8 ° (c=1g/dL, H2O).
Embodiment 2: (1S, 4R) preparation of 4-amino cyclopentyl-sour methyl esters of 2-alkene-1-(midbody 2)
(1S, 4R) 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester 110g and Boc acid anhydride 86.7g are suspended in the 143.0g methyl alcohol with L-tartrate.Add triethylamine 88.0g at 30-35 ℃, add the amine of half amount after, reaction solution clarification, and begin to emit CO2 gas.After adding whole amine, with solution stirring 2h.This solution is cooled to 5-10 ℃, keeps reacting liquid temperature to be no more than 10 ℃, add 25% ammoniacal liquor 5.5g and 420ml water.Add a small amount of (1S, 4R) 4-[[1,1-dimethyl-oxyethyl group) carbonyl] amino]-2-cyclopentenes-1-carboxylate methyl ester crystal is as crystal seed, obtains white precipitate.Mixture stirs 2h at 5-10 ℃, filters, and filters solid and uses water washing, reduces pressure 35-40 ℃) drying.Obtain target compound 82.5g, 90.5%, mp51.3-52.0 ℃; [α] D20 ℃=-52.5 ° (c=1g/dL, H2O).
The preparation of embodiment 3:2-ethyl butyraldehyde oxime (midbody 3)
Earlier oxammonium hydrochloride salt 52.0g is dissolved in the water of 400ml, again to wherein adding people 65.0g, salt of wormwood, 20-25 ℃ is stirred 1h, temperature control 0-5 ℃ slowly drips 2-ethyl butyraldehyde 65.0g slowly, ethanolic soln 350ml.After dropwising, 20-25 ℃ is stirred 1h.Concentrating under reduced pressure, gained oily matter add 325 gram methylene dichloride, washing again, the saturated common salt washing, anhydrous Na 2SO4 is dry, concentrate colorless oil 52.6g, yield 70.
Embodiment 4: (3aR, 4R, 6S, 6aS)-and { [(1,1-dimethyl-oxyethyl group) carbonyl] amino }-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene is [d] isoxzzole-6-carboxylic acid 2 also, the preparation of 2-dimethyl ethyl ammonium (midbody 4)
Under the lucifuge condition, (94.7g2-ethyl butyraldehyde oxime (midbody 3) is put in the heptane of 315g, is cooled to 0-5 ℃, drips 9.8% chlorine bleach liquor 882g with 3-4h for 1S, 4R) 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester (midbody 2) with 90g.Be warming up to 20-30 ℃ after dropwising and continue reaction 6h,, filter; The gained white solid adds methyl alcohol 360g, stirs, and temperature control drips 30% aqueous sodium hydroxide solution 75g below 30 ℃; Reaction 2-3h drips concentrated hydrochloric acid and transfers Ph=4, adds entry 600g dilute reaction solution; Add MTBE and extract water layer, aqueous phase discarded 500g*3 time.Merge organic phase, anhydrous magnesium sulfate drying filters, and filtrating adds TERTIARY BUTYL AMINE 23g at 22-28 ℃; Mixture stirs 3h, filters, and filter cake is with the drip washing of 120g MTBE, 60 ℃ of dry 10h of normal pressure; Get target compound 129.6g, yield 84%, mp:186.5-187.8 ℃.
Embodiment 5: (3aR, 4R, 6S, 6aS)-and { [(1,1-dimethyl-oxyethyl group) carbonyl] amino }-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene is [d] isoxzzole-6-carboxylic acid 2 also, the preparation of 2-dimethyl ethyl ammonium (midbody 4)
(1S, 4R) 4-amino cyclopentyl-2-alkene-1-carboxylate methyl ester (midbody 2) is dissolved in toluene (310g) and triethylamine 62.9g, and this reaction mixture is heated to 60-70 ℃ with 50g.In this solution, add the toluene solution of 2-ethyl-N-hydroxyl imido butyryl chloride (93.0g) with 2.5h, form white solid deposition (triethylamine hydrochloride).After adding, reaction mixture continues to stir 5h at 60-70 ℃.Reaction mixture is cooled to 20-25 ℃, filters and remove deposition, with toluene 50g washing leaching cake.Merging filtrate is in 15 ℃ of water with sodium hydroxide 12.4g (37.3g) solution-treated.Temperature slowly rises to 30 ℃.Water 294g dilutes this reaction mixture, and layering.Water 50g extracted organic phase, the water after the merging extracts with toluene 50g.Add MTBE 250g to aqueous phase, the pH of this reaction mixture is transferred to 4.0 with concentrated hydrochloric acid 26.1g.After being separated, with MTBE 250g aqueous phase extracted.Merge organic phase, use dried over mgso.The filtering siccative washs with MTBE 50g.Merging filtrate, with MTBE 250g dilution, and with TERTIARY BUTYL AMINE 15.2g 20-25 ℃ of processing.Product is the white solid deposition.Mixture stirs 3h, filters collecting precipitation then, and with MTBE 75g washing, 40 ℃ of dry 16h get target compound 54.0g, yield 63%.
Embodiment 6: (3aR, 4R, 6S, 6aS)-(+)-4-{ [(1,1-dimethyl-oxyethyl group) carbonyl] amino }-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene is the preparation of [d] isoxzzole-6-carboxylate methyl ester (midbody 5) also
With 54g (3aR, 4R, 6S, 6aS)-{ [(1; 1-dimethyl-oxyethyl group) carbonyl] amino }-3-(1 '-ethyl propyl)-3a, 5,6,6a-tetrahydrochysene-4H-pentamethylene is [d] isoxzzole-6-carboxylic acid 2 also; 2-dimethyl ethyl ammonium (midbody 4) is suspended among the methyl alcohol 115g, adds trimethyl orthoformate 16.6g; Reaction mixture is cooled to 5-10 ℃, and dripping thionyl chloride 9.7g in reaction mixture, reacting liquid temperature are no more than 20 ℃; Mixture becomes clear soln.This solution stirs 2-3h at 20-25 ℃.Add Boc acid anhydride 7.1g, stir 5min, add then triethylamine 6.5g with pH regulator to 8-9.This solution stirring is cooled to 10 ℃ then to 30min, adds the dilution of 25% ammoniacal liquor 3.5g and 100g water.In solution, add crystal seed and stir 15-30min, add 25% ammoniacal liquor 3.5g and 100g water again, this suspension-s is cooled to 0-5 ℃, restir 2h.Filter and collect product, water 150g washing, 45-50 ℃ of vacuum-drying gets target compound 44g, yield 95.0%, purity 99.6%.
Embodiment 7: (1S, 2S, 3S, 4R, 1 ' S)-3-[(1 '-amino-2 ' ethyl) butyl]-4-{ [(1,1-dimethyl-oxyethyl group) carbonyl] amino }-preparation of 2-hydroxy-cyclopentane-1-carboxylate methyl ester (midbody 6)
Two (2-methoxy ethoxy) sodium aluminate toluene solution (the red aluminum solutions) 65.2 of the dihydro of 70% weight are mixed with 220g toluene, be cooled to 10-15 ℃, drip (3aR, 4R; 6S, 6aS)-(+)-4-{ [(1,1-dimethyl-oxyethyl group) carbonyl] amino }-3-(1 '-ethyl propyl)-3a, 5; 6,6a-tetrahydrochysene-4H-pentamethylene is toluene (380g) solution of [d] isoxzzole-6-carboxylate methyl ester (midbody 5) 40g also, drips to finish to be warming up to 80-90 ℃ of reaction 5h, adds sal glauberi 20.0g; Stir 45-60min, filtered while hot, filtrating adds saturated EDTA two sodium water solution 350g, is warming up to 75-80 ℃ and stirs 60min; Divide the phase of anhydrating while hot, organic phase is cooled to 5-10 ℃ with 2h, stirs 2h, filters; Filter cake is with toluene 200g drip washing, and the 40-50 ℃ of drying that reduce pressure gets target compound 32.7g, yield 80.8%.
Embodiment 8: (1S, 2S, 3S, 4R, 1 ' S)-3-[(1 '-amino-2 ' ethyl) butyl]-4-{ [(1,1-dimethyl-oxyethyl group) carbonyl] amino }-preparation of 2-hydroxy-cyclopentane-1-carboxylate methyl ester (midbody 6)
100g midbody 5 and Nickel dichloride hexahydrate 72.2 are dissolved in methyl alcohol 280g, are cooled to 0-5 ℃, methyl alcohol (230g) solution of dropping sodium 0.5g and Peng Qinghuana 28.0 is added dropwise to reaction mixture at 0-5 ℃ with 2h.After the hydroborate solution addition, reaction mixture stirs 30min at 0-5 ℃.Add Sodium Nitrite 25g, ammonium chloride 58g and 25% ammoniacal liquor 65g, the solution that the aqueous solution forms in water (650g), temperature of reaction is no more than 25 ℃.The black solid dissolving forms mazarine suspension-s.This mixture stirs 12-16h at 20-25 ℃.Filter collecting precipitation, with 25% ammoniacal liquor (150g) water (900g) solution washing 2 times.Filter cake is suspended in the toluene (1800g) and 25% ammoniacal liquor (130g) aqueous solution.This suspension-s discards the blue-greenish colour water at 70-80 ℃ of heating 1h, in organic phase, adds 25% ammoniacal liquor (150g) aqueous solution, 70-80 ℃ of heating, and aqueous phase discarded adds two ethylenediamine hydrate Sequestrene AAs (EDTA) water (200g) solution (15g).70-80 ℃ of heating 1h is separated, and with 2-3h organic layer is cooled to 0-5 ℃, behind the stirring 2-3h, filters and collects product, washs with toluene (200g).Wet product gets target compound 69.8g, yield 69% 40-50 ℃ of vacuum-drying.
Embodiment 9: the preparation of RWJ 270201 bullion
With (1S, 2S, 3S, 4R, 1 ' S)-3-[(1 '-amino-2 ' ethyl) butyl]-4-{ [(1,1-dimethyl-oxyethyl group) carbonyl] amino }-2-hydroxy-cyclopentane-1-carboxylate methyl ester (midbody 6) 67.0g, be suspended in the 530g toluene, be cooled to 0-5 ℃.Drip acetic anhydride 22.2g, reaction solution stirring at room 1h is transparent settled solution.Use water (150g) the solution washing organic phase of yellow soda ash 16.1g then.Aqueous phase discarded at 0-5 ℃, is added to organic phase in the 73.7g concentrated hydrochloric acid with 5min, and 5-10 ℃ is stirred 1h, and layering is with 40g water washing organic phase.Merge water, temperature control 0-5 ℃ drips 30% aqueous sodium hydroxide solution 118g, with pH regulator to 12.5.Drip and finish at 0-10 ℃ of restir 1h.At 25-30 ℃, add hydrochloric acid 1,2,4-triazole-1-carbonamidine 34.2g.This suspension stirs 30min, adds 30% aqueous sodium hydroxide solution pH is transferred to 8.4, and 20-25 ℃ is stirred 12-14h.This suspension is cooled to 0-5 ℃, restir 2-3h.Filter and collect product, water (30g) washing.Product gets target compound 49.8g, yield 81.2% through dry air.
Embodiment 10: the preparation of RWJ 270201 finished product
RWJ 270201 bullion 45 is suspended in the 160g water, adds 31.5g methyl alcohol, stir and be warming up to 70-80 ℃, add gac 2.3g.With this reaction mixture reflux 30min, use the silica gel filtered while hot.Filter cake is used the 8g methanol wash.Merging filtrate, reflux once more, evaporating solvent reaches 99-100 ℃ until boiling point.This mixture is cooled to 70-80 ℃, during be settled out product.This mixture is stirred 12-16h at 70-80 ℃, be cooled to 0-5 ℃.Solid collected by filtration, with 15g cold water (0-10 ℃) washing, dry air gets target compound 44g, yield 84%, purity: 99.90%, moisture 14.12%.
Claims (8)
1. the preparation method of a RWJ 270201 comprises the steps:
1). step (a) gets midbody 1 with 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone with chlorinating agent open loop, fractionation, salify, protects amino midbody 2 again;
2). step (b) with 2-ethyl butyraldehyde and oxammonium hydrochloride react midbody 3;
3). step (c) is in Youxiaolin/non-polar solvent system, with the cyclization of step (a)/(b) gained midbody, hydrolysis, acidifying, salify resterification midbody 5;
4). step (d) midbody 5 reductive ring open under the reductive agent effect gets midbody 6;
5). step (e) midbody 6 gets midbody 7 through acetylize, deaminizating protection, hydrolysis, last carbonamidine again;
6). step f) midbody 7 recrystallizations get the RWJ 270201 finished product.
2. preparation method according to claim 1, wherein, the described chlorinating agent of step (a) is selected from sulfur oxychloride; Described resolving agent is selected from tartrate, camphorsulfonic acid, glycocoll;
3. preparation method according to claim 1, wherein, step (c) comprising: midbody 3 and midbody 2 are mixed in the non-polar solvent; Drip the chlorine bleach liquor, addition cyclization under certain temperature, basic hydrolysis in alcoholic solvent again; Acidifying; Use organic solvent extraction, after make it become tert-butylamine salt, esterification gets midbody 5;
4. according to claim 1 or 3 described preparing methods, the described non-polar solvent of step (c) is selected from hexanaphthene, sherwood oil, heptane, toluene; Described ring-closure reaction temperature is-10-20 ℃; Described alcoholic solvent is selected from methyl alcohol, ethanol, Virahol, propyl carbinol; Described acidifying is acidifying under hydrochloric acid, sulfuric acid, formic acid, acetic acid existence condition; Described alkali is selected from sodium hydroxide, Pottasium Hydroxide, yellow soda ash, salt of wormwood, sodium hydrogencarbonate; Described organic solvent is selected from methylene dichloride, chloroform, acetonitrile, ETHYLE ACETATE, ethyl formate, MTBE, toluene;
5. preparation method according to claim 1, wherein, the described reductive agent of step (d) is selected from Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN, lithium aluminium hydride, (2-methoxy ethoxy) sodium aluminate toluene solution (red aluminum solutions).
6. preparation method according to claim 1, wherein, the described deaminizating of step (e) protection is meant to be carried out under hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, Hydrogen bromide existence condition;
7. preparation method according to claim 1, wherein, step (f) described recrystallization is meant and in the mixed solvent of alcoholic solvent and water, carries out, most preferably, is selected from the methanol mixed solvent.
8. according to the described preparation method of claim 1 to 7, most preferably, the preparation method of described RWJ 270201 comprises the steps:
Step a): with 2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone with the sulfur oxychloride open loop after esterification, split salify through tartrate again, midbody 1, amino the midbody 2 of protection midbody 1;
Step b):, generate midbody 3 with 2-ethyl butyraldehyde and oxammonium hydrochloride reaction;
Step c): in Youxiaolin/heptane system, hydrolysis under cyclization, alkaline condition, acidifying, again with the TERTIARY BUTYL AMINE salify, midbody 4; Midbody 4 gets midbody 5 through free, esterification;
Step d): midbody 5 in red aluminum solutions, reduce midbody 6;
Step e): midbody 6 gets midbody 7 through acetylize, deaminizating protection, hydrolysis, last carbonamidine;
Step f): recrystallization midbody 7 gets the RWJ 270201 finished product.
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Application publication date: 20120815 |